Nebivolol ((±)-[(S,R,R,R)±(R,S,S,S)-]-α,α′-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzo-pyran-2-methanol]) and its pharmaceutically active HCl salt—as disclosed in U.S. Pat. No. 4,654,362 A and its counter EP 0145067 A2—is a potent and selective β1 adrenergic blocker used for treatment of high blood pressure. Nebivolol*HCl (nebivolol hydrochloride) is applied as a racemate and consists of the two enantiomers: d-nebivolol*HCl and l-nebivolol*HCl.

Numerous syntheses for the preparation of nebivolol hydrochloride have been disclosed, for example in U.S. Pat. No. 4,654,362 A (JANSSEN), EP 0334429 A1 (JANSSEN), WO 2004/041805 A1 (EGIS), WO 2006/016376 A1 and WO 2007/083318 A1 (HETERO DRUGS), WO 2006/025070 A2 (TORRENT), WO 2008/010022 A2 (CIMEX), WO 2008/064826 A2 and WO 2008/064827 A2 (ZACH), WO 2009/082913 A1, CN 101463024 A, WO 2010/049455 (ZACH) and WO 2010/089764 A1 (ZACH).
The challenge in each process for the manufacture of Nebivolol or its pharmaceutically active HCl salt is its unique structure as Nebivolol contains four chiral centers resulting in 16 theoretical isomers. In fact, the total number of diastereomers is reduced to only 10 due to the symmetry plane through the N atom of the molecule. As a consequence, this symmetry plane provokes similar retrosynthetic cuts in most of the published syntheses.
Not surprisingly, most of the reported processes apply the reaction of 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran building blocks of the formula A (Scheme 1) of appropriate stereochemistry with formally ammonia, a suitably protected primary amine or azide ion.

Besides other methods, suitable precursors of epoxides of formula A are chloroalcohols B
reported for the first time in EP 1803715 A1. Usually, chloroalcohols can be synthesized from chloroketones of formula C
which themselves can be prepared from chromane carboxylic acids, such as 6-fluoro-chroman-2-yl-carboxylic acid, according to known techniques (see for example EP 1803715 A1, U.S. Pat. No. 7,650,575 B2).
In WO 2011/091968 A1 we disclosed a highly stereoselective approach for the synthesis of racemic nebivolol (racemic mixture of d-nebivolol and l-nebivolol) as well as for the production of the individual enantiomers d-nebivolol and l-nebivolol based on enantiomerically pure chloroketones and chloroalcohols.
The synthesis is performed according the general scheme 2.

For example, d-nebivolol Fa was prepared by enzymatic reduction of 1-(2S)-(6-fluorochroman-2-yl)-2-chloroethan-1-one Ca and 1-(2R)-(6-fluorochroman-2-yl)-2-chloroethan-1-one Cb to give either the S- or the R-configurated chloroalcohol Ba or Bb. (S)-2-chloro-1-((R)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethanol Ba was subjected to amination by treatment with sodium methoxide followed by reaction with benzylamine to give (S)-2-benzylamino-1-((R)-6-fluoro-3,4-dihydro-2H-chronnen-2-yl)ethanol Da. This underwent coupling with (R)-2-chloro-1-((R)-6-fluoro-3,4-dihydro-2H-chronnen-2-yl)ethanol Bb followed by debenzylation to give d-nebivolol Fa. An analogue pathway applies if Bb was subjected to amination. l-Nebivolol Fb was produced in a similar way. Finally, d- and l-nebivolol (Fa and Fb) were mixed to give racemic nebivolol G which can be converted to the hydrochloride salt.
Chloroketones C can be prepared from chromane carboxylic acids according to known techniques, e.g. WO 2008010022 A2 (Cimex) describes the conversion of 6-fluoro-chromanic acid to the corresponding acid chloride, followed by reaction with Meldrum's acid with the aid of a base. We found this process unsatisfactory when starting with enantiomerically pure 6-fluoro-chromanic acid since the base induced partial isomerisation.
Other known processes for the preparation of chloroketones (for example WO 2010/034927 A1) suffer from more general aspects as the processes are based on organometallic chemistry. These processes need strong cryogenic conditions and are not feasible for industrial production from an economical point of view.
It is evident that partial isomerisation of the chloroketones C will result in lower diastereomerical purity of chloroalcohols B which leads to the formation of unwanted nebivolol diastereomers in the coupling step. This has an impact not only on the yield but also on quality of nebivolol.
The goal of the present invention is to provide a more suitable access to enantiomerically pure chloroketones which can be used in the manufacture of nebivolol and, thus, providing an economic access to Nebivolol in a high yield and high quality.